Diazepinoindoles as phosphodiesterase 4 inhibitors

Abstract

Diazepinoindoles of formula (I), ##STR1## wherein A is mono- to trisubstituted aryl or heteroaryl, and B is an --OR 1 or --NR 2 R 3 group where R 1 , R 2 and R 3 are particularly hydrogen, and racemic forms, enantiomers and pharmaceutically acceptable salts thereof, as phosphodiesterase IV inhibitors, are disclosed.

We claim: 
     
       1. A compound of formula (1) ##STR15## containing from one to four nitrogen atoms, each A optionally being substituted with one to three groups chosen independently from halogen, lower alkyl haloallyl lower alkoxy, cycloalkyloxy, amino, lower alkylcarbonylamino or lower alkyloxycarbonylamino; B is:   ° ) --OR 1 , R 1  being --H or R 4 ,   2°) --NR a  R b , R a  being --C(NH)NH 2  and R b  being --H,   3°) --NR c  R d , R c  being R 4  and R 4  being --H,   4°) --NR e  R f , R e  and R f  independently being --H or lower alkyl, or   5°) --N--R 2  --R 3 , R 2  and R 3  forming, together with the nitrogen atom to which they are attached, a saturated five- to seven-membered heterocycle which may comprise, as second hetero atom not attached directly to the nitrogen atom, an oxygen, a sulfur or a nitrogen; R 4  is:     1°) --CH 2  --CO 2  H   2°) --CO--(CH 2 ) p  --CO 2  H,   3°) --CO--A, where A has the definition indicated above,   4°) --CO--CH═CH--CO 2  H,   5°) --CO--(CH 2 ) n  --CH 3 , n being an integer equal to or greater than 0 and less than or equal to 18,   6°) --CO--(CH 2  --O--CH 2 ) p  --CH 2  --O--CH 3 ,   7°) --CO--(CH 2  --O--CH 2 ) p  --CO 2  H,   8°) --(CH 2 ) p  --NR 5  R 6 , R 5  and R 6  independently being --H or lower alkyl or   9°) --(CH 2 ) p  --N--R 5  --R 6 , R 5  and R 6  forming, together with the nitrogen atom to which they are attached, a saturated five- to seven-membered heterocycle which may comprise, as second hetero atom not attached directly to the nitrogen atom, an oxygen, a sulfur or a nitrogen; p is an integer equal to 2, 3 or 4; the racemic forms and isomers thereof of configuration determined in particular by carbon 3 of the diazepinoindol-4-one ring, as well as the pharmaceutically acceptable salts thereof.     
     
     
       2. A compound of formula (1) according to claim 1, characterized in that their absolute configuration is R according to the Cahn-Igold-Prelog rule, considering the asnmmetric carbon atom in an alpha position relative to the carbonyl of the diazepine ring. 
     
     
       3. A compound of formula (1) according to claim 1, characterized in that B is OR 1  or NR 2  R 3  where R 1  R 2  R 3  are hydrogen. 
     
     
       4. A compound of formula (I) according to claim 1, in which A is aryl substituted with one to 3 groups independently chosen from halogen, amino and lower alkoxy. 
     
     
       5. A compound of formula (I) according to claim 1, in which A is monocyclic nitrogen-containing heteroaryl comprising from 1 to 2 nitrogen atoms or bicyclic nitrogen-containing heteroaryl comprising from 1 to 4 nitrogen atoms. 
     
     
       6. A compound of formula (1) according to claim 5, in which A is heteroaryl substituted with amino, lower alkyl, lower alkyloxycarbonylamino or alkylcarbonylamino groups. 
     
     
       7. A compound ofthe formula (II) ##STR16## in which B is OR 1  or NR 2  R 3 , R 1 , R 2  and R 3  being hydrogen. 
     
     
       8. Process for the preparation of the compounds (I) ##STR17## according to claim 1, characterized in that it consists: a) In order to obtain the compounds (Ib) of formula (I) in which B is an --OH group: in acylating an aminodiazepinoindole (II b ) of formula (II), in which B is an --OH group, with a reactant (III) of formula Z--CO--A, in which A is nitrogen-containing aryl or heteroaryl, each optionally substituted with one to three groups independently chosen from halogen, lower alkyl, lower haloalkyl, lower alkoxy, cycloalkyloxy, amino, lower alkyloxycarbonylamino or lower alkylcarbonylamino, and Z represents a halogen, a hydroxyl group, an azido group, an imidazol-1-yl group or a group --O--CO--Z 1 , it being possible for Z 1  to be, besides A, a bulky alkyl or alkoxy radical containing from 3 to 6 carbon atoms, or alternatively Z may be a group O--Z 2 , Z 2  being an aromatic group containing one or two rings substituted with one or more nitro or halo radicals, or     in O-demethylating, in position 9 of the diazepinoindole ring, an intermediate compound (I' c ) of formula ##STR18## with a boron or aluminum halide, or in diazotizing, in a first step, a compound (I e ) of formula (I), in which B is an --NH 2  group, and then in hydrolyzing, in a second step, the intermediate diazonium salt, and b) in order to obtain the compounds (I e ) of the invention, of formula (I), in which B is an --NH 2  group,     in acylating a compound (II e ) of f ormula (II), in which B is an --NH 2  group, with the reactant (III) defined in a) of this claim, or   in reducing the nitro radical of an intermediate compound (I' d ) of formula ##STR19## by the action of a metal such as Zn or Sn in acidic medium, or that of a metal chloride or sulfide such as TiCi 3  or Na 2  S, and c) in order to obtain the compounds (I bb ) of the invention, of formula (I), in which B is a group --O--CO--V; V being a group chosen from:     A, as defined in a) of this claim,   (CH 2 ) p  --CO 2  H, where p is an integer equal to 2, 3 or 4,   CH═CH--CO 2  H,   (CH 2 ) n  --CH 3 , where n is an integer equal to or greater than 0 and less than or equal to 18,   (CH 2  --O--CH 2 ) p  --CH 2  --O--CH 3 , where p is an integer equal to 2, 3 or 4, or   (CH 2  --O--CH 2 ) p  --CO 2  H, where p is an integer equal to 2, 3 or 4, in esterifying a compound (I b ) defined in a), with a reactant (III') of formula V--CO--Z, in which Z has the meaning defined in a) of this claim, and   d) in order to obtain the compounds (I bc ) of the invention, of formula (I), in which B is a group --O--R 4 , R 4  being a group chosen from:     --CH 2  --CO 2  H,   --(CH 2 ) p  --NR 5  R 6 , where R 5  and R 6  are independently --H or lower alkyl, or   --(CH 2 ) p  --N--R 5  --R 6 , where R 5  and R 6  form, together with the nitrogen atom to which they are attached, a heterocycle, in reacting a compound (I b ), defined in a), with a strong base such as an alkali metal hydride, in order to form a phenate, which is reacted with a halide XR 4 , and e) in order to obtain the compounds (I ea ) of the invention, of formula (I), in which B is a group --NH--C (NH) --NH 2 ,   in reacting a compound (I e ), defined in b), with a guanylating agent such as cyanamide, and   f) in order to obtain the compounds (I eb ) of the invention, of formula (I), in which B is a group --NH--CO--V, V having the meaning defined in c) of this claim, in amidating a compound (I e ), defined in b), with the reactant (III'): V--CO--Z defined in c) of this claim, and   g) in order to obtain the compounds (I ec ) of the invention, of formula (I), in which B is a group --NH--R 2 , R being lower alkyl or a group R 4  as defined in d) of this claim,   in reacting a compound (Ie) defined in b), in the presence of a strong base with an alkyl halide XR 2 , and   h) in order to obtain the compounds (I ed ) of the invention, of formula (I), in which B is a group --NR 2  R 3 , R 2  and R 3  being lower alkyls,   in performing the reductive alkylation of a compound (I ec ), defined in g) of this claim, with an aldehyde R' 3  CHO, in which R' 3  is the immediately lower homolog of R 3 , and   i) in order to obtain the compounds (I ee ) of the invention, of formula (I), in which B is a group --N--R 2  --R 3 , R 2  and R 3  forming a heterocycle,   in carrying out a cyclization by reaction of a compound (I e ), defined in b), with a reactant of formula     X--(CH.sub.2).sub.1 --Q--(CH.sub.2).sub.m --X'     in which X and X', which may be the same or different, are halogens, Q is:     a single valency bond, and 1 and m are integers ranging from 1 to 3 with l+m greater than or equal to 4 and less than or equal to 6,   an oxygen, a sulfur or a group --NH--, in which case l and m are integers ranging from 1 to 3 with l+m greater than or equal to 3 and less than or equal to 5, or, in alkylating an intermediate diazepinoindole (II f ) of formula II wherein B is a group --N--R 2  --R 3 , R 2  and R 3  forming with the nitrogen atom a heterocycle, with a reactant (III) of formula Z--CO--A as previously defined.   
     
     
       9. A method for the treatment of inflammation in a subject which comprises administering to said subject a therapeutically effective amount of a diazepinoindole according to claim 1. 
     
     
       10. A method for the treatment of inflammation in a subject which comprises administering to said subject a therapeutically effective amount of a diazepinoindole according to claim 1. 
     
     
       11. The compound: (3R)-Isoquinoline-3-carboxylic acid (9-hydroxy-4-oxo-1-phenyl-3,4,6,7-tetrahydro-[1,4]diazepino [6,7,1-hi]indol-3-yl) amide;   (3R)-4-t-Butyloxycarbonylamino-N-(9-amino-4-oxo-1-phenyl-3,4,6,7,-tetrahydro [1,4]diazepino [6,7,1-hi]indol 3-yl) benzamide;   (3R)-4-Amino-N-(9-amino-4-oxo-1-phenyl-3,4,6,7-tetrahydro [1,4]diazepino [6,7,1-hi]indol-3-yl) benzamide;   (3R)-4-Amino-N-(9-Amino-4-oxo-1-phenyl-3,4,6,7-tetrahydro [1,4]diazepino [6,7,1-hi]indol-3-yl)-3,5-dichlorobenzamide;   (3R)-4-Amino-N-[9-(4-amino-3,5-dichlorobenzamido) -4-oxo-1-phenyl-3,4,6,7-tetrahydro [1,4]-diazepino [6,7,1-hi]indol-3-yl]-3,5-dichlorobenzamide;   (3R)-2-Acetylamino-N-(9-amino-4-oxo-1-phenyl-3,4,6,7-tetrahydro [1,4]diazepino [6,7,1-hi]indol-3-yl) benzamide;   (3R) - N-(9-Amino-4-oxo-1-phenyl-3,4,6,7-tetrahydro [1,4]diazepino [6,7,1-hi]indol-3-yl)-2-methoxybenzamide;   (3R)-4-Amino-N-(9-amino-4-oxo-1-phenyl-3,4,6,7-tetrahydro [1,4]diazepino 6,7,1-hi]indol-3-yl)-5-chloro-2-methoxybenzamide;   (3R)-N-(9-Amino-4-oxo-1-phenyl-3,4,6,7-tetrahydro [1,4]diazepino [6,7,1-hi]indol-3-yl-3-cyclopentyloxy-4-methoxybenzamide;   (3R)-Pyridine-2-carboxylic acid (9-amino-4-oxo-1-phenyl-3,4,6,7-tetrahydro [1,4]diazepino [6,7,1-hi]indol-3-yl) amide;   (3R)-N-(9-Amino-4-oxo-1-phenyl-3,4,6,7-tetrahydro [1,4]diazepino [6,7,1,-hi]indol-3 -yl-isonicotinamide;   (3R)-3-t-Butyloxycarbonylamino-N-(9-amino-4-oxo-1-phenyl-3,4,6,7-tetrahydro [1,4 ]diazepino [6,7,1-hi]indol-3-yl) isonicotinamide;   (3R)-3-Amino-N-(9-amino-4-oxo-1-phenyl-3, 4, 6, 7-tetrahydro [1,4]diazepino [6,7,1-hi]indol-3-yl)isonicotinamide;   (3R)-3-Acetylamino-N-(9-acetylamino-4-oxo-1-phenyl-3,4,6,7-tetrahydro [1,4]diazepino-[6,7,1-hi]indol-3-yl)isonicotinamide;   (3R) -N-(9-Amino-4-oxo-1-phenyl -3,4,6,7-tetrahydro [1,4]diazepino[6,7,1-hi]indol-3yl-)-3,5-dichloroisonicotinamide;   (3R)-Pyrazine-2-carboxylic acid (9-arnino-4-oxo -1-phenyl-3,4,6,7-tetrahydro [1,4]diazepino [6,7,1-hi]indol-3-yl)amide;   (3R)Isoquinoline-3-carboxylic acid (9-amino-4-oxo-1-phenyl-3,4,6,7-tetrahydro [1,4]-diazepino [6,7,1-hi]indol-3-yl) amide;   (3R)-Quinoline-3-carboxylic acid (9-amino-4-oxo-1-phenyl-3,4,6,7-tetrahydro [1,4]-diazepino [6,7,1-hi]indol-3-yl)amide;   (3R)-4,7-Dimethylpyrazolo [5,1-c][1,2,4]triazine-3-carboxylic acid (9-amino-4-oxo-1-phenyl-3,4,6,7-tetrahydro [1,4]diazepino [6,7,1-hi]indol-3-yl )amide;   (3R)-4-Amino-3,5-dichloro-N-(9-dirnethylamino-4-oxo-1-phenyl-3,4,6,7-tetrahydro [1,4]-diazepino [6,7,1-hi]indol-3-yl) benzamnide;   (3R)-4-Amino-3,5-dichloro-N-(4-oxo-1-phenyl -9-pyrrolidin-1-yl-3,4,6,7-tetrahydro [1,4]-diazepino [6,7,1-hi]indol-3-yl)benzamide;   (3R)-4-Amino-3,5-dichloro-N-(4-oxo-1-phenyl-9-morpholin-1-yl-3,4,6,7-tetrahydro [1,4]-diazepino [6,7,1-hi]indol-3-yl)benzamide;   (3R)-4-Amino-3,5-dichloro-N-(9-quanidino-4-oxo-1-phenyl-3,4,6,7-tetrahydro [1,4]-diazepino [6,7,1-hi]indol-3-yl)benzamide;   (3R)-N-(9-Acetylamino-4-oxo-1-phenyl-3,4,6,7-tetrahydro [1,4] diazepino [6,7,1-hi]indol-3-yl)-4-amino-3, 5-dichlorobenzamide;   (3R)-4-Amino-3,5-dichloro-N-(9-{2-[2-(2-methoxyethoxy)ethoxy]acetylamino}-4-oxo-1-phenyl-3,4,6,7-tetrahydro [1,4]diazepino-[6,7,1-hi]indol-3-yl)benzamide;   (3R)-(2-{2-[3-(4-Amino-3,5-dichlorobenzoyl-amnino)-4-oxo-1-phenyl-3,4,6,7-tetrahydro[1,4]diazepino [6,7,1-hi]indol-9-ylcarbamoyl-methoxy]ethoxy}ethoxy) acetic acid;   (3R)-Hexadecanoic acid [3-(4-amino-3,5-dichlorobenzoylamino)-4-oxo-1-phenyl-3,4,6,7-tetrahydro [1,4]diazepino[6,7,1-hi]indol-9-ylamide;   (3R)-Isoquinoline-3-carboxylic acid (9-acetylamino-4-oxo-1-phenyl-3,4,6,7-tetrahydro [1,4]diazepino [6,7,1-hi]indol-9-yl) amide;   (3R)N-(9-amino-4-oxo-1-phenyl-3,4,6,7-tetrahydro [1,4]diazepino [6,7,1-hi]indol-3-yl-2-benzofuranecarboxamide;   (3R)N-[4-oxo-1-phenyl-9-(pyrrolidin-1-yl)-3,4,6,7-tetrahydro [1,4]diazepino [6,7,1-hi]indol-3-yl)-isonicotinamide; or   (3R)-4,7-dimethyl-pyrazolo [5,1-c][1,2,4]triazine-3-carboxylic acid [4-oxo-1-pheny-9-(pyrrolidin-1-yl)-3,4,6,7-tetrahydro [1,4]diazepino [6,7,1-hi]indol-3-yl-amide.   
     
     
       12. The compound: (3R)-N-(9-amino-4-oxo-1-phenyl-3,4,6,7-tetrahydro [1,4 ]diazepino [6,7,1-hi]indol-3-yl) nicotinamide.   
     
     
       13. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier. 
     
     
       14. A pharmaceutical composition comprising a compound of claim 11 and a pharmaceutically acceptable carrier. 
     
     
       15. A pharmaceutical composition comprising a compound of claim 12 and a pharmaceutically acceptable carrier. 
     
     
       16. A method for the treatment of inflammation in a subject which comprises administering to said subject a therapeutically effective amount of a compound of claim 11. 
     
     
       17. A method for the treatment of inflammation in a subject which comprises administering to said subject a therapeutically effective amount of a compound of claim 12. 
     
     
       18. A method for the treatment of asthma in a subject which comprises administering to said subject a therapeutically effective amount of a compound of claim 1. 
     
     
       19. A method for the treatment of asthma in a subject which comprises administering to said subject a therapeutically effective amount of a compound of claim 11. 
     
     
       20. A method for the treatment of asthma in a subject which comprises administering to said subject a therapeutically effective amount of a compound of claim 12. 
     
     
       21. A method for the treatment of allergies in a subject which comprises administering to said subject a therapeutically effective amount of a compound of claim 1. 
     
     
       22. A method for the treatment of allergies in a subject which comprises administering to said subject a therapeutically effective amount of a compound of claim 11. 
     
     
       23. A method for the treatment of allergies in a subject which comprises administering to said subject a therapeutically effective amount of a compound of claim 12.